Construction of furan-fused cyclobutanone and synthetic applications as a reactive and versatile building block

A Rh-catalyzed [3+2] annulation involving a 4-exo-dig carbocyclization process has been disclosed, which provides a direct access to unknown furan-fused cyclobutanone scaffolds. This unique molecule can participate in a variety of ring-opening transformations as a versatile synthon.
Construction of furan-fused cyclobutanone and synthetic applications as a reactive and versatile building block
Like

Cyclobutanone is a strained cyclic motif that is present in many natural products, bioactive molecules, and materials. Benzocyclobutenones (BCBs), which possess higher ring strain than saturated cyclobutanones due to their rigid planar architectures, are versatile building blocks for the transition-metal-mediated C-C bond activation to access diverse skeletons that are nontrivial to synthesize otherwise1,-3. Although many efforts have been devoted to the synthesis of BCB skeletons in the past few decades, the construction of cyclobutanones that are fused to nonbenzene aromatics remains an uncharted area in synthetic chemistry.

Fig. 1 | Catalytic cycloaddition & cyclization methods. a Catalytic carbocyclization & carbene/alkyne metathesis (CAM). b This study: catalytic 4-exo-dig carbocyclization process for the direct construction of furan-fused cyclobutanones vs competitive 5-endo-dig cyclization.

In the past two decades, transition-metal complex catalyzed alkyne carbocyclization has emerged as a powerful method in organic synthesis for the direct construction of carbocyclic and heterocyclic structures from different functionalized alkyne precursors. In this context, the carbene/alkyne metathesis (CAM)4,5 cascade reaction is one of the elegant cyclization protocols for the straightforward preparation of 5- and 6-membered carbocyclic structures through different types of exo- or endo-dig cyclizations (Fig. 1a, path e-h). However, the 4-exo-dig cyclization process is certainly the least-explored one, and no successful example has been disclosed thus far (Fig. 1a, path i), which might be due to the competitive 5-endo-dig pathway that was proposed to be more sterically favorable.

As continuing our interests in catalytic alkyne functionalization6-8, we were curious about the feasibility of enabling an uncharted catalytic 4-exo-dig cyclization process for the direct construction of four-membered structures. To the best of our knowledge, the catalytic 4-exo-dig carbocyclization of alkynes for the construction of cyclobutanones has not been reported. Herein, we present our recent results in this direction, a Rh-catalyzed formal [3+2] annulation of diazo group tethered alkynes involving a 4-exo-dig carbocyclization process. This methodology provides direct and convenient access to the synthesis of furo[3,4-b]cyclobutanones via an intramolecular annulation of the in-situ formed zwitterionic intermediates rather than through a CAM process involving vinyl carbene species (Fig. 1b, path j). In our protocol, a vinylic sp2-hybridized carbon has been introduced as the key linkage of the diazo group and the triple bond, instead of using a flexible aliphatic chain, which could facilitate the 4-exo-dig carbocyclization by bringing the reacting centers in close proximity. Thus, one of the serious drawbacks, the inherent propensity of the competitive 5-endo-dig carbocyclization of alkynes towards thermodynamically stable tricyclic products through the endocyclic carbene intermediates, could be overcome (path k). Moreover, density functional theory (DFT) computation elucidates that the favorable 4-exo-dig cyclization is mainly attributed to the relatively lower angle strain of the key sp-hybridized vinyl cationic transition state in the cyclization step. The synthesized cyclobutanone-fused furan derivatives with imbedded furyl, carbonyl, and benzylidene motifs have not been previously reported and are potential versatile synthetic building blocks. This practical method could be successfully applied for the late-stage modification of complex natural products and pharmaceutical molecules, and the synthetic application of these unique compounds has been demonstrated through a variety of ring-opening reactions and cycloadditions for the diversity-oriented-synthesis. Continuing works on the exploration of novel catalytic transformations with this intriguing furan-fused cyclobutanone as a 4C synthon in cycloaddition reactions, including the asymmetric catalytic version, are going on in the lab and will be reported soon.

References

  1. Xue, Y. & Dong, G. Deconstructive synthesis of bridged and fused rings via transition metal-catalyzed “cut-and-sew” reactions of benzocyclobutenones and cyclobutanones. Acc. Chem. Res. 55, 2341–2354 (2022).
  2. Murakami, M. & Ishida, N. Cleavage of carbon−carbon σ‑bonds of four-membered rings. Chem. Rev. 121, 264−299 (2021).
  3. Sietmann, J. & Wahl, J. M. Enantioselective desymmetrization of cyclobutanones: a speedway to molecular complexity. Angew. Chem. Int. Ed. 59, 6964–6974 (2020).
  4. Torres, Ò. & Pla-Quintana, A. The rich reactivity of transition metal carbenes with alkynes. Tetrahedron Lett. 57, 3881−3891 (2016).
  5. Pei, C., Zhang, C., Qian, Y. & Xu, X. Catalytic carbene/alkyne metathesis (CAM): a versatile strategy for alkyne bifunctionalization. Org. Biomol. Chem. 16, 8677–8685 (2018) and the references cited therein.
  6. Bao, M., Zhou, S., Hu, W. & Xu, X. Recent advances in gold-complex and chiral organocatalyst cooperative catalysis for asymmetric alkyne functionalization. Chinese Chem. Lett. 33, 4969–4979 (2022).
  7. Zhou, S., Li, Y., Liu, X., Hu, W., Ke, Z. & Xu, X. Enantioselective oxidative multi-functionalization of terminal alkynes with nitrones and alcohols for expeditious assembly of chiral α-alkoxy-β-amino-ketones. J. Am. Chem. Soc. 143, 14703−14711 (2021).
  8. Dong, G., Bao, M., Xie, X., Jia, S., Hu, W. & Xu, X. Asymmetric allylation by chiral organocatalyst-promoted formal hetero-ene reactions of alkylgold intermediates. Angew. Chem. Int. Ed. 60, 1992–1999 (2021).

Please sign in or register for FREE

If you are a registered user on Research Communities by Springer Nature, please sign in

Subscribe to the Topic

Chemistry
Physical Sciences > Chemistry

Related Collections

With collections, you can get published faster and increase your visibility.

Pre-clinical drug discovery

We welcome studies reporting advances in the discovery, characterization and application of compounds active on biologically or industrially relevant targets. Examples include emerging screening technologies, the development of small bioactive compounds/peptides/proteins, and the elucidation of compound structure-activity relationships, target interactions and mechanism-of-action.

Publishing Model: Open Access

Deadline: Mar 31, 2024

Biomedical applications for nanotechnologies

Overall, there are still several challenges on the path to the clinical translation of nanomedicines, and we aim to bridge this gap by inviting submissions of articles that demonstrate the translational potential of nanomedicines with promising pre-clinical data.

Publishing Model: Open Access

Deadline: Dec 31, 2023